Dovlatova N L, Jakubowski J A, Sugidachi A, Heptinstall S
Cardiovascular Medicine, University of Nottingham, Nottingham, UK.
J Thromb Haemost. 2008 Jul;6(7):1153-9. doi: 10.1111/j.1538-7836.2008.03020.x. Epub 2008 Jul 1.
Agents that act as antagonists at P2Y(12) ADP receptors on platelets are in use (clopidogrel), and in development for use (cangrelor and prasugrel), in patients with cardiovascular disease. Cangrelor is a direct-acting reversible antagonist being developed for short-term infusion; clopidogrel and prasugrel are oral prodrugs that provide irreversible inhibition via transient formation of active metabolites. At the cessation of cangrelor infusion, patients are likely to receive clopidogrel or prasugrel as a means of maintaining antiplatelet therapy.
To apply an experimental in vitro approach to investigate the possibility that cangrelor influences the ability of the active metabolites of clopidogrel and prasugrel to inhibit ADP-mediated platelet function.
The effects of cangrelor and the active metabolites of clopidogrel (C-AM) and prasugrel (P-AM) on platelet function were assessed by ADP-induced platelet P-selectin expression in whole blood. The method involved rapid removal of the antagonists by dilution, and measurement of residual platelet inhibition.
Cangrelor, C-AM and P-AM markedly inhibited P-selectin expression. The effect of cangrelor, but not of C-AM and P-AM, was reversible following antagonist removal. Preincubation of blood with cangrelor prior to addition of C-AM or P-AM reduced the ability of metabolites to irreversibly antagonize P2Y(12). Irreversible inhibition was maintained when blood was preincubated with metabolites prior to cangrelor.
Cangrelor influences the ability of the active metabolites of clopidogrel or prasugrel to inhibit platelet function irreversibly. Careful consideration should be given to the timing of administration of an oral P2Y(12) antagonist following cangrelor infusion.
作为血小板P2Y(12) ADP受体拮抗剂的药物正在心血管疾病患者中使用（氯吡格雷），并处于研发阶段（坎格雷洛和普拉格雷）。坎格雷洛是一种正在研发用于短期输注的直接作用可逆拮抗剂；氯吡格雷和普拉格雷是口服前体药物，通过活性代谢产物的短暂形成提供不可逆抑制作用。在停止输注坎格雷洛后，患者可能会接受氯吡格雷或普拉格雷作为维持抗血小板治疗的手段。
应用实验性体外方法研究坎格雷洛是否会影响氯吡格雷和普拉格雷的活性代谢产物抑制ADP介导的血小板功能的能力。
通过全血中ADP诱导的血小板P-选择素表达评估坎格雷洛以及氯吡格雷（C-AM）和普拉格雷（P-AM）的活性代谢产物对血小板功能的影响。该方法包括通过稀释快速去除拮抗剂，并测量残留的血小板抑制作用。
坎格雷洛、C-AM和P-AM均显著抑制P-选择素表达。去除拮抗剂后，坎格雷洛的作用可逆，而C-AM和P-AM的作用不可逆。在添加C-AM或P-AM之前用坎格雷洛预孵育血液会降低代谢产物不可逆拮抗P2Y(12)的能力。当在添加坎格雷洛之前用代谢产物预孵育血液时，不可逆抑制作用得以维持。
坎格雷洛会影响氯吡格雷或普拉格雷的活性代谢产物不可逆抑制血小板功能的能力。在输注坎格雷洛后给予口服P2Y(12)拮抗剂时应仔细考虑给药时间。
